**1. Introduction**

Immunization plays a key role in maintaining human health as it saves millions of lives in the most economical way from lethal pathogens and other fatal diseases each year, thanks to the advanced development of model vaccines, which are biological preparations containing an antigenic agent that resembles a disease-causing microorganism to stimulate the host's immune system, thus providing active acquired immunity to a particular disease and destroying it [1, 2]. Since Jenner's pioneering inoculations in the late eighteenth century, vaccines have been successfully developed to combat various diseases and each year saved numerous lives from, mostly, lethal infections and now also certain cancers [3, 4]. Especially, taking advantage of the tools discovered in microbiology and immunology, vaccines have recently obtained great achievements as demonstrated by their successful performances in conquering some formidable pathogens, such as smallpox and rabies, which are used to claim many lives. However, the list of pathogens for which there exist no vaccines is still long, and, in particular, many pathogens, such as human immunodeficiency virus (HIV), herpes simplex virus (HSV), and Ebola virus (EBV), are still posing a big threat to human life, therefore needing urgently the effective products to cope with their infections [5].

Vaccines can stimulate the host immune system to develop an armament of immunity capable of clearing the abnormalities after administration, because they are developed with the antigenic components that are featured by pathogens or neoplasms and usually include three types: the live attenuated microbes, killed microbes, and just purified antigens (Ags) of microbes or neoplasms [6]. The former two consisting of live attenuated or killed microbes are the conventional vaccines with high immunogenicity but, unfortunately, are also linked to a relatively poor safety profile as they possess the potential to revert the virulence and induce the drifted immune responses leading to incontrollable immunity as well as unacceptable inflammations. In contrast, the third one with purified Ags, called a subunit vaccine, has

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

defined components to induce immune responses aiming just at the matched targets causing few safety concerns and thus can be employed to fight the infectious pathogens as well as malignant neoplasms that are carrying the identical Ags [7]. Presently, subunit vaccines are attracting more and more research interests owing to also their diverse applications, adaptive functions, and numerous advantages over the whole microbe-based conventional ones, and these aspects may well be comprehensively summarized as follows [8]:

the immune system and (2) binding to PRRs and exciting the innate immune cells, such as DCs, MPs, histiocytes, and mast cells, which subsequently initiate the innate immune responses to sponsor the subsequent adaptive immune responses [22, 23]. Accordingly, vaccine adjuvants may well be classified into two types: type I, the natural or synthetic substances with intrinsic adjuvanticity, squalene/squalane, saponin, chitosan, hyaluronic acid (HA), and various pattern recognition receptor agonists (PRRas) and type II, the micron-/nanometer-sized particles, such as alum (insoluble aluminum salt) and vaccine adjuvant-delivery systems (VADSs) that are carriers engineered with at least two fundamental functions, i.e., adjuvanticity and Ag delivery. VADSs are usually constructed with a variety of biocompatible nanoparticles (NPs) made of various organic or inorganic materials, such as liposomes, ISCOMs (immunestimulating complexes), polymeric NPs, VLPs (virus-like particles), emulsions, and the inorganic NPs, which are often incorporated with type I substances to further enhance their

Introductory Chapter: Immunization - Vaccine Adjuvant Delivery System and Strategies

http://dx.doi.org/10.5772/intechopen.81981

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**2. Immune responses for establishing the Ag-specific immunity**

Always confronting and fighting with dangerous pathogens, mammals have gradually evolved to form a complexed defensive immune system, which can be classified into subsystems of the innate immune system versus the adaptive immune system [25]. The innate immune system consists of surface barriers, complement system, and various leukocytes including the phagocytes (macrophages, neutrophils, and dendritic cells), innate lymphoid cells, mast cells, eosinophils, basophils, and natural killer cells, which fulfill the role of non-specific immune defenses responding to pathogens in a generic way conferring short-lasting immunity against a pathogen [26]. For this, mammalian leukocytes are evolutionarily equipped with receptors able to recognize certain pathogen components bearing specific structural characteristics, such as free bacterial and viral DNA, lipoproteins, lipopolysaccharides, and flagellins, which are pathogen-/danger-associated molecular patterns (PAMPs/DAMPs) [27]. These functional receptors are expressed by host immune cells, such as TLR1 to TLR13, NOD-like receptors, RIG-I-like receptors, and C-type lectin of mannose receptors, which are collectively called pattern recognition receptors (PRRs), with each capable of selectively binding to specific PAMPs/DAMPs of pathogens, leading to the activation of the innate immune cells, which subsequently sponsor the immunoresponses of the whole immune system, thus providing the bases for defending against

However, establishing the Ag-specific immunity for defending against pathogens involves several complex immune pathways going with the orchestration of numerous immunocytes, cytokines, and chemokines and starts, usually, upon the activation of APCs for innate immune reactions triggered by their internalized antigenic substances (Ags) that they distinguished as dangerous signals through, in most cases, the process of PRR-PAMP/DAMP recognition [23]. Briefly, positioned at the frontier of pathogen/vaccine recognition, APCs first take up, in a size-dependent manner (e.g., NPs with a size of <150 nm are taken up by APCs by clathrinmediated endocytosis, while microparticles by phagocytosis); the Ags appeared in peripheral tissues or in the draining lymph nodes (dLNs), wherein APCs will mature and process the

immunopotentiating functions [6, 24].

pathogens [28].


However, unfortunately, subunit vaccines often have a rather weak immunogenicity, due to lack of the immunostimulatory components broadly shared by pathogens while being distinguishable from host molecules, which are collectively referred to as pathogen-associated molecular patterns (PAMPs) [15] able to bind to and trigger mammalian pattern recognition receptors (PRRs), such as the TLRs (toll-like receptors), NOD-like receptors (the nucleotidebinding oligomerization domain-like receptors), RIG-I-like receptors (retinoic acid-inducible gene-I-like receptor), and C-type lectin receptors, thus playing an adjuvant role to activate the innate immunity, followed by sponsoring a series of adaptive reactions involved in establishing the Ag-specific immunity [16].

Thus, while subunit vaccines are regarded as a safer product than the whole microbe-based conventional ones, they are also poorly immunogenic and often require an adjuvant or a vaccine adjuvant-delivery system (VADS) able to target the professional Ag-presenting cells (APCs), such as dendritic cells (DCs) and macrophages (MPs), to make full use of Ags and boost their immunostimulatory activity [17–21]. A vaccine adjuvant is defined as a non-specific immunopotentiating substance but capable of enhancing the body's immune response to the Ag or changing the type of immune responses, when administered either alone in advance or simultaneously together with the vaccine Ag. Although its immune-boosting mechanisms remain elusive, an adjuvant is argued to fulfill the functions involving, roughly, two aspects: (1) generating damages on host cells/tissues, thus sending dangerous signals out to activate the immune system and (2) binding to PRRs and exciting the innate immune cells, such as DCs, MPs, histiocytes, and mast cells, which subsequently initiate the innate immune responses to sponsor the subsequent adaptive immune responses [22, 23]. Accordingly, vaccine adjuvants may well be classified into two types: type I, the natural or synthetic substances with intrinsic adjuvanticity, squalene/squalane, saponin, chitosan, hyaluronic acid (HA), and various pattern recognition receptor agonists (PRRas) and type II, the micron-/nanometer-sized particles, such as alum (insoluble aluminum salt) and vaccine adjuvant-delivery systems (VADSs) that are carriers engineered with at least two fundamental functions, i.e., adjuvanticity and Ag delivery. VADSs are usually constructed with a variety of biocompatible nanoparticles (NPs) made of various organic or inorganic materials, such as liposomes, ISCOMs (immunestimulating complexes), polymeric NPs, VLPs (virus-like particles), emulsions, and the inorganic NPs, which are often incorporated with type I substances to further enhance their immunopotentiating functions [6, 24].
